Journal of

Clinical Medicine

Article
The Conditions Under Which Piracetam Is Used and
the Factors That Can Improve National Institute of
Health Stroke Scale Score in Ischemic Stroke Patients
and the Importance of Previously Unnoticed Factors
From a Hospital-Based Observational Study
in Taiwan
Shu-Yi Chen 1,2,† , Jai-Wen Liu 3 , Yu-Hsun Wang 4 , Jing-Yang Huang 4 ,
Shiuan-Chih Chen 1,5,6 , Shun-Fa Yang 1,4,† and Po-Hui Wang 1,4,5,7, *
1 Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road,
Taichung 40201, Taiwan; shuyichen2008@gmail.com (S.-Y.C.); sccy399@yahoo.com.tw (S.-C.C.);
ysf@csmu.edu.tw (S.-F.Y.)
2 Department of Neurology, Tung’s Taichung MetroHarbor Hospital, No.699, Sec. 8, Taiwan Blvd.,
Taichung 40201, Taiwan
3 Department of Emergency Medicine, Chung Shan Medical University Hospital, 110, Section 1, Chien-Kuo
North Road, Taichung 40201, Taiwan; jwliuh@gmail.com
4 Department of Medical Research, Chung Shan Medical University Hospital, 110, Section 1, Chien-Kuo North
Road, Taichung 40201, Taiwan; cshe731@csh.org.tw (Y.-H.W.); wchinyang@gmail.com (J.-Y.H.)
5 School of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road,
Taichung 40201, Taiwan
6 Department of Family and Community Medicine, Chung Shan Medical University Hospital, 110, Section 1,
Chien-Kuo North Road, Taichung 40201, Taiwan
7 Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, 110, Section 1,
Chien-Kuo North Road, Taichung 40201, Taiwan
* Correspondence: wang082160@gmail.com; Tel.: +886-4-24739595 (ext. 21721); Fax: +886-4-24738493
† These authors contributed equally to this work.




Received: 18 December 2018; Accepted: 17 January 2019; Published: 20 January 2019


Abstract: This study aimed to explore the associations of piracetam use and the clinical characteristics
of NIHSS (National Institute of Health Stroke Scale) changes—the importance of which, as prognosis
related factors, was previously unnoticed—and analyze the associations of piracetem with NIHSS
changes by stratifying clinical characteristics. This observational retrospective study was conducted
by enrolling patients based on 2483 stroke registration data cohorts from a 1200-bed regional Tungs’
Taichung MetroHarbor Hospital, located in central Taiwan from 1 January 1 2011 to 31 December 2015.
Patients were excluded if they had intravenous a thrombolytic agent within 3 hours of symptoms
onset (n = 49), incomplete or erroneous NIHSS scores (n = 953), or transient ischemia stroke (n
= 130). Logistic regression model was applied for associating piracetam treatment and clinical
characteristics with NIHSS score changes between admission and discharge, and subgroup analysis
to assess the conditions under which piracetam can be used. Multivariate analysis revealed NIHSS
scores improvement in atrial fibrillation, large-artery atherosclerosis, underweight, current smoker,
ex-smoker, and piracetam. Subgroup analysis showed piracetam is beneficial in the following:
age ≥75 years olds, males, those of normal weight, those who are obese, ex-smokers, those with
hypertension, dyslipidemia, those without diabetes mellitus, nor atrial fibrillation. The selection
of the conditions under which piracetam treatment should be given, and clinical characteristics, is
important for NIHSS improvement of ischemic stroke patients in Taiwan.

J. Clin. Med. 2019, 8, 122; doi:10.3390/jcm8010122 www.mdpi.com/journal/jcm

J. Clin. Med. 2019, 8, 122 2 of 13

Keywords: piracetam; clinical characteristics; acute ischemic stroke; National Institute of Health
Stroke Scale; atrial fibrillation; subgroup analysis

1. Introduction
Ischemic stroke is a major cause of death in developed countries, and the leading cause
of long-term disability in survivors. The Ministry of Health and Welfare of Taiwan reported
cerebrovascular accidents as the fourth leading cause of death in 2017. A complex series of biochemical
reactions occur which may lead to the death of brain cells. Two major types of therapeutic approaches
to acute ischemic stroke have been raised [1]. Firstly, thrombolytics were suggested because they
could act to restore cerebral blood flow. Current effective treatments for acute ischemic stroke are
intravenous thrombolytic therapy within 4.5 h of onset and intra-arterial thrombectomy within 6
h of onset [2]. Secondly, neuroprotectants were suggested because they target cellular biochemical
pathways to preserve brain function, enhance neuronal repair, and promote recovery. However, there is
no conclusive evidence supporting the use of various other drugs claiming neuroprotective effects [2].
Piracetam (2-Oxo-1-pyrrolidineacetamide), the first representative of the nootropic drugs, is a
cyclic derivative of gamma-aminobutyric acid (GABA) [3]. It may increase compromised regional
cerebral blood flow and oxygen utilization in brain, and permeability of cell and mitochondrial
membrane to intermediates of the Krebs cycle [4]. Piracetam has been found to exert neuroprotective
action and offer protection from brain neuron death or cell damage on experimental animals [5,6].
It presents antioxidative antiapoptotic activity and may restore altered neuronal morphology and
decrease neuronal density, which were caused by lipopolysaccharides [5]. In addition, piracetam seems
to display neuroprotective properties in hemorrhagic shock models [7]. It is approved by the Taiwan
Food and Drug Administration for use in acute cardiovascular disease, but the efficacy of piracetam
use in patients with acute stroke has yet to be proven. Therefore, in the current environment, and with
a better treatment standard, there is room for discussion of the association of piracetam treatment with
ischemic stroke patients.
A prespecified hypothesis was therefore raised that piracetam treatment and some clinical
variables are associated with ischemic stroke patients’ neurological improvement, as assessed by
National Institutes of Health Stroke Scale (NIHSS) score in Taiwan. Their associations with NIHSS
improvement, however, are not investigated in Taiwan. Although they were unnoticed previously
in Taiwan, the piracetam treatment and the factors that may improve NIHSS score in acute ischemic
stroke patients were very important for patient prognosis and should be delineated. The aims of this
study were to explore the associations of piracetam use as well as clinical characteristics with NIHSS
score changes for acute ischemic stroke patients in Taiwan. In addition, the unique features of this
study were to further analyze the conditions under which piracetam can be given to improve NIHSS
score by stratifying the epidemiological and comorbidity characteristics.

2. Materials and Methods

2.1. Source of Data and Study Cohort

This observational and retrospective cohort study was conducted by collecting 2483 ischemic
stroke patients who were admitted to the intensive care unit (ICU) of Tungs’ Taichung MetroHarbor
Hospital, a 1200-bed regional teaching hospital located in central Taiwan, from 1 January 2011 to 31
December 2015, and retrospectively reviewed and analyzed from the stroke registration database
of the hospital. The study was conducted in accordance with the Declaration of Helsinki, and the
protocol was approved by the Institutional Review Board of Tungs’ Taichung MetroHarbor Hospital
(107019, V2/2018-05-17). All subjects gave their informed consent. Criteria for ICU admission were
based on recommendations of the American College of Critical Care Medicine and the Society of
J. Clin. Med. 2019, 8, 122 3 of 13

J. Clin. Med. 2019, 8, x FOR PEER REVIEW

Critical Care Medicine [8]. Patients were excluded if they had an intravenous thrombolytic 3agent of 13

(recombinant tissue plasminogen activator, rt-PA, Actilyse) within 3 hours of symptom onset (n = 49),
incomplete or erroneous admission or discharge NIHSS scores (n = 953), or transient ischemia stroke
incomplete or erroneous admission or discharge NIHSS scores (n = 953), or transient ischemia stroke
(n = 130) (Figure 1). Of the 1351 cases included in the study, in addition to basic fluid therapy for these
(n = 130) (Figure 1). Of the 1351 cases included in the study, in addition to basic fluid therapy for these
patients, 457 received intravenous piracetam (trade name: Nootropil 200 mg/mL, 5 mL/amp; Nang
patients, 457 received intravenous piracetam (trade name: Nootropil 200 mg/mL, 5 mL/amp; Nang
Kuang Pharmaceutical, Taipei, Taiwan) 1 g every 8 h for 3 days and the remaining 894 did not. The
Kuang Pharmaceutical, Taipei, Taiwan) 1 g every 8 h for 3 days and the remaining 894 did not. The
piracetan was not randomized to give. No placebo was given. However, patients were not aware
piracetan was not randomized to give. No placebo was given. However, patients were not aware
whether piracetam was given or not. The epidemiological and comorbidity characteristics of patients
whether piracetam was given or not. The epidemiological and comorbidity characteristics of patients
with piracetam and without piracetam were assessed if they were balanced based on standardized
with piracetam and without piracetam were assessed if they were balanced based on standardized
difference. This study evaluates the association of piracetam treatment with the NIHSS score changes
difference. This study evaluates the association of piracetam treatment with the NIHSS score changes
between the admission and discharge date for patients with acute ischemic stroke.
between the admission and discharge date for patients with acute ischemic stroke.

Figure 1. Flowchart of enrollment procedures for the study. A total of 2483 cases were registered
Figure the
during 1. Flowchart of enrollment
study period procedures
and 1351 patients for the study.
were recruited A total oftreatment
into piracetam 2483 cases wereand
group registered
control
during the study period and 1351 patients were recruited into piracetam treatment group
group after the exclusion of those receiving intravenous thrombolytic agent within 3 h of symptoms and control
group after the exclusion of those receiving intravenous thrombolytic agent within 3 h of symptoms
onset (n = 49), those having incomplete or erroneous admission or discharge NIHSS score (n = 953) and
onset having
those (n = 49), those having
transient incomplete
ischemia stroke (n or erroneous
= 130). NIHSS,admission
National or discharge
Institute NIHSSStroke
of Health score Scale.
(n = 953)
and those having transient ischemia stroke (n = 130). NIHSS, National Institute of Health Stroke Scale.
The NIHSS score was defined previously in [9]. Sample size was calculated based on the
Thefor
analysis NIHSS score was defined
the association previously
of piracetam in [9]. Sample
treatment with NIHSSsize was calculated
score change. based on theerror
The alpha analysis
(α)
for the association of piracetam treatment with NIHSS score change. The alpha error
was determined to be 0.05; the beta error (β), 0.2; power, 0.8 (1-beta error). The needed total sample (α) was
determined
size was 1248,to as
be calculated
0.05; the beta error (β),
according to 0.2;
the power,
following0.8 formula:
(1-beta error). Thehypothesis):
H0 (null needed totalpsample
1 = p2 ; size
HA
was 1248, as
(alternative calculatedp1according
hypothesis): 6= p2 to the following formula: H0 (null hypothesis): p1 = p2; HA
1 ≠ p2
(alternative hypothesis): p
q 2

p
Zα/2 2P 1 − P + Zβ p1 (1 − p1 ) + p2 (1 − p2 )
N𝑍 = / 2 P 1− P +𝑍 𝑝21−𝑝 +𝑝 1−𝑝
( p1 − p2 )
N=
𝑝 −𝑝
αα == 0.05, Zα/2
0.05, Z α/2==1.96;
1.96;β β ZβZ=β0.842
= 0.2,
= 0.2, = 0.842
pp11: NIHSS improved rate of piracetam treatment;
treatment; pp22: NIHSS
NIHSS improved rate of no piracetam treatment;
PP= =(p + p2)/2
(p11+p 2 )/2
J. Clin. Med. 2019, 8, 122 4 of 13

2.2. Definition of Epidemiological and Comorbidity Variables

The epidemiological and clinical variables include: admission and discharge NIHSS scores,
gender, age, hypertension, diabetes mellitus, dyslipidemia, body mass index (BMI), smoking habits,
atrial fibrillation, and TOAST (Trial of Organization 10,172 in Acute Stroke Treatment) classification of
subtype of acute ischemic stroke [10]. The main evaluators of NIHSS score are Neurology specialists,
qualified through training and videotape test based on the National Institute of Neurological Disorders
and Stroke (NINDS) trials [11]. BMI values are analyzed according to the World Health Organization
(WHO) definition: <18.5 (underweight), 18.5 to 24.9 (normal weight), 25 to 29.9 (overweight), and ≥30
kg/m2 (obese) [12]. Hypertension is defined as systolic blood pressure more than 140 mmHg [13],
and diabetes mellitus is diagnosed by fasting blood glucose >126 mg/dL or HbA1c >6.5% (American
Diabetes Association, 2010). A system for classification of ischemic stroke was developed for the
Trial of Organization 10,172 in Acute Stroke Treatment. The TOAST classification denotes five
subtypes of ischemic stroke based on etiology: large-artery atherosclerosis, small-vessel occlusion,
cardioembolism, stroke of other determined etiology, and stroke of undetermined etiology [11]. The
last two classifications were grouped together in the study. The criteria for dyslipidemia included those
who are receiving lipid-lowering drugs or require intervention: low-density lipoprotein >100 mg/dL,
or triglyceride >160 mg/dL [14].
For TOAST classification, all patients received an electrocardiogram test, echocardiography,
carotid sonography, and transcranial doppler for intracranial large blood vessels flow evaluation. All
patients received neuroimaging examination: 90.3% received brain computed tomography (CT), 80%
brain magnetic resonance imaging (MRI). Twenty four-hour Holter monitor or electrocardiogram
telemetry record for 72 h was done for those suspected of embolic stroke. Based on the above
information, a neurologist determines the patient’s TOAST classification. CT perfusion requires
hardware and software components that are not widely available. The institution where this study was
performed does not have the equipment necessary for CT perfusion. In the determination of TOAST
classification, which mainly requires brain MRI and complete cardiovascular evaluation, CT perfusion
was not applied. In addition, CT perfusion can evaluate the areas of decreased blood flow, but it is not
necessarily compatible with the area of acute infarction being treated at the time. In this study, the
patients who did not receive MRI evaluation, of whom acute infarction area could not be determined
on a brain CT, or of whom transcranial doppler sonography could not show cerebral artery stenosis,
were placed in the fourth classification: undetermined or other causes.

2.3. Outcomes
The primary endpoints were to evaluate the associations of piracetam use as well as
epidemiological and comorbidity factors with NIHSS score changes and further to determine the
conditions under which piracetam improved NIHSS scores. Subtraction of discharge NIHSS score
by admission NIHSS score was done. The NIHSS score is a tool used by healthcare providers to
objectively quantify the neurological impairment caused by a stroke [15]. A comparison of admission
and discharge NIHSS scores greater than 4 at discharge is considered significant improvement [15,16];
otherwise, not improvement.

2.4. Statistical Analysis

A standardized difference of more than 10% was used to detect significant piracetam subgroups
imbalance between baseline epidemiological and comorbidity variables [17]. Chi-square test was
applied to evaluate the associations of piracetam use as well as epidemiological and clinical variables
with NIHSS score changes. The multivariate analysis and subgroup analysis were done using logistic
regression model with further adjustment for multiple baseline covariates as the piracetam/no
piracetam baseline balance might be violated within subgroups. Odds ratios (ORs) and their 95%
confidence intervals (CIs) were calculated using logistic regression model. Sensitivity analysis was
J. Clin. Med. 2019, 8, 122 5 of 13

done for possible interaction among piracetam and other covariates. The adjusted risk (ratio) difference
in favor of improvement in NIHSS between piracetam and no piracetam subgroups, and among other
variable subgroups, was determined based on logistic regression model. The difference was calculated
as I0 × (AOR-1), for which AOR is the adjusted odds ratio in the case subgroup and I0 the unadjusted
odds (instead of incidence in reference 17) for patients in the control subgroup [18]. Therefore, the
adjusted ratio difference was calculated as control subgroup odds × (case subgroup AOR-1). All
analyses were performed with PASW Statistics 18. All p values were 2-sided and a p value <0.05
indicated a statistical significance.

3. Results

3.1. Balance of Piracetam and no Piracetam Subgroups between Baseline Epidemiological and
Comorbidity Characteristics
Of the 1351 ischemic stroke patients included in the study, 457 (33.8%) received intravenous
piracetam. The mean admission NIHSS score of our database was 6.5 and the NIHSS score was
improved in 131 (9.7%) of all patients. Based on the TOAST classification, the patients were grouped
into small-vessel occlusion 432 (32.0%), large-artery atherosclerosis 406 (30.0%), embolic stroke 193
(14.3%), and stroke of other etiology 320 (23.7%). The patients who received piracetam treatment
were older (piracetam/ no piracetam: 72.0 ± 12.2/70.5 ± 12.5, p = 0.031). No statistically significant
differences were noted among other categories (Table 1). No significant imbalance was noted between
piracetam and no piracetam subgroups for baseline epidemiological and comorbidity variables based
on most standardized differences being no more than 10% (Table 1).

Table 1. Baseline epidemiological and comorbidity characteristics of ischemic stroke patients receiving
piracetam versus those not receiving piracetam in Taiwan.

Piracetam No Piracetam Standardized

Characteristics p Value
n = 457 (%) n = 894 (%) Difference
Age (years)
mean ± SD 72.0 ± 12.2 70.5 ± 12.5 0.031 0.130
Age (years)
<75 246 (53.8%) 523 (58.5%)
0.101 0.095
≥75 211 (46.2%) 371 (41.5%)
Gender
male 295 (64.6%) 577 (64.5%)
0.960 0.002
female 162 (35.4%) 317 (35.5%)
BMI
underweight 17 (3.8%) 39 (4.5%) 0.035
normal weight 243 (52.0%) 421 (48.1%) 0.078
0.564
overweight 160 (35.6%f) 328 (37.5%) 0.039
obese 39 (8.7%) 87 (9.9%) 0.041
Smoking
non-smoker 272 (59.5%) 559 (62.5%) 0.061
current smoker 138 (30.2%) 229 (25.6%) 0.179 0.103
ex-smoker 47 (10.3%) 106 (11.9%) 0.051
Hypertension
negative 88 (19.3%) 190 (21.3%)
0.390 0.050
positive 369 (80.7%) 704 (78.7%)
Diabetes mellitus
negative 252 (55.1%) 449 (50.2%)
0.087 0.094
positive 205 (44.9%) 445 (49.8%)
J. Clin. Med. 2019, 8, 122 6 of 13

Table 1. Cont.

Piracetam No Piracetam Standardized

Characteristics p Value
n = 457 (%) n = 894 (%) Difference
Dyslipidemia
negative 127 (27.8%) 290 (32.4%)
0.080 0.100
positive 330 (72.2%) 604 (67.6%)
Atrial fibrillation
negative 370 (81.0%) 737 (82.4%)
0.505 0.036
positive 87 (19.0%) 157 (17.6%)
TOAST
small-vessel occlusion 135 (29.5%) 297 (33.2%) 0.080
large-artery atherosclerosis 140 (30.6%) 266 (29.8%) 0.017
0.558
cardioembolism 70 (15.3%) 123 (13.8%) 0.043
others 112 (24.5%) 208 (23.3%) 0.028
Statistical analysis: chi-square test and Student’s t test. Abbreviations: SD, standard deviation; BMI, body mass
index; TOAST, Trial of Organization 10,172 in Acute Stroke Treatment classification.

3.2. The Factors Associated with Ischemic Stroke Based on Univariate Analysis
Univariate analysis was performed for the associations of piracetam use as well as epidemiological
and comorbidity variables with NIHSS score changes in ischemic stroke patients (Table 2).

Table 2. Univariate and multivariate analyses for the associations of piracetam treatment as well as
epidemiological and comorbidity factors with changes of NIHSS score in ischemic stroke patients
in Taiwan.

Group Group
Univariate Multivariate
A–NIHSS B–NIHSS Not
Variables Analysis p Value Analysis p Value
Improved (>4) Improved (≤4)
OR (95% CI) OR (95% CI)
n = 131 (%) n = 1220 (%)
Age (years)
<75 56 (42.7%) 713 (58.4%) 1.00 1.00
<0.001 0.053
≥75 75 (57.3%) 507 (41.6%) 1.88 (1.31–2.71) 1.52 (1.00–2.33)
Gender
male 46 (35.1%) 443 (35.5%) 1.00 1.00
0.932 0.437
female 85 (64.9%) 787 (64.5%) 1.02 (0.70–1.48) 0.82 (0.50–1.35)
BMI
underweight 59 (46.5%) 596 (49.7%) 1.00 0.002 1.00 0.026
normal weight 14 (11.0%) 42 (3.6%) 3.37 (1.74–6.52) <0.001 3.05 (1.47–6.30) 0.003
overweight 45 (35.4%) 443 (37.0%) 1.03 (0.68–1.54) 0.901 1.11 (0.72–1.70) 0.644
obese 9 (7.1%) 117 (9.8%) 0.78 (0.38–1.61) 0.498 0.93 (0.44–2.00) 0.858
Smoking
non-smoker 70 (53.4%) 761 (62.4%) 1.00 0.083 1.00 0.017
current smoker 40 (30.5%) 327 (26.8%) 1.33 (0.88–2.00) 0.172 1.81 (1.07–3.06) 0.026
ex-smoker 21 (16.0%) 132 (10.8%) 1.73 (1.03–2.91) 0.039 2.29 (1.22–4.28) 0.009
Piracetam
negative 72 (55.0%) 822 (67.4%) 1.00 1.00
0.005 0.005
positive 59 (45.0%) 398 (32.6%) 1.69 (1.18–2.44) 1.73 (1.18–2.55)
Hypertension
negative 29 (22.1%) 249 (20.4%) 1.00 1.00
0.642 0.465
positive 102 (77.9%) 971 (79.6%) 0.90 (0.58–1.39) 0.84 (0.52–1.35)
Diabetes mellitus
negative 76 (58.0%) 625 (51.2%) 1.00 1.00
0.141 0.468
positive 55 (42.0%) 595 (48.8%) 0.76 (0.53–1.10) 0.86 (0.58–1.29)
Dyslipidemia
negative 43 (32.8%) 374 (30.7%) 1.00 1.00
0.610 0634
positive 88 (67.2%) 846 (69.3%) 0.91 (0.62–1.33) 1.11 (0.37–1.69)
Atrial fibrillation
negative 82 (62.6%) 1025 (84.0%) 1.00 1.00
<0.001 <0.001
positive 49 (37.4%) 195 (16.0%) 3.14 (2.14–4.62) 3.92 (2.31–8.24)
J. Clin. Med. 2019, 8, 122 7 of 13

Table 2. Cont.

Group Group
Univariate Multivariate
A–NIHSS B–NIHSS Not
Variables Analysis p Value Analysis p Value
Improved (>4) Improved (≤4)
OR (95% CI) OR (95% CI)
n = 131 (%) n = 1220 (%)
TOAST
small-vessel occlusion 21 (16.0%) 411 (33.7%) 1.00 <0.001 1.00 <0.001
large-artery atherosclerosis 51 (38.9%) 355 (29.1%) 2.81 (1.66–4.77) <0.001 2.68 (1.57–4.60) <0.001
cardioembolism 34 (26.0%) 159 (13.0%) 4.19 (2.36–7.43) <0.001 0.87 (0.38–1.96) 0.933
others 25 (19.1%) 295 (24.2%) 1.66 (0.91–3.02) 0.098 1.06 (0.56–2.02) 0.640
Statistical analysis: chi-square test and logistic regression model. Abbreviations: NIHSS, National Institute of Health
Stroke Scale; BMI, body mass index; TOAST, Trial of Organization 10,172 in Acute Stroke Treatment classification;
OR, odds ratio; 95% CI, 95% confidence interval.

Comparison was made between those with improvement of NIHSS and those without. Univariate
analysis showed increased odds ratio in favor of improvement in NIHSS score for age ≥75 years old
(OR: 1.88, 95% CI: 1.31–2.71; p < 0.001), underweight with BMI <18.5 (OR: 3.37, 95% CI: 1.74–6.52;
p < 0.001), ex-smoker (OR: 1.73, 95% CI: 1.03–2.91; p = 0.039), piracetam treatment (OR: 1.69, 95% CI:
1.18–2.44; p = 0.005), atrial fibrillation (OR: 3.14, 95% CI: 2.14–4.62; p < 0.001), large-artery atherosclerosis
(OR: 2.81, 95% CI: 1.66–4.77; p < 0.001), and cardioembolism (OR: 4.19, 95% CI: 2.36–7.43; p < 0.001).
Hypertension, diabetes mellitus, and dyslipidemia showed no association with NIHSS improvement.

3.3. The Factors Associated with Ischemic Stroke Based on Multivariate Analysis
We performed a multivariate analysis of piracetam administration and clinical characteristics on
NIHSS improvement in ischemic stroke patients (Table 2). Multivariate analysis showed significant
associations of NIHSS score changes with the following subgroups: underweight (OR: 3.05, 95% CI:
1.47–6.30; p = 0.003), current smoker (OR: 1.81, 95% CI: 1.07–3.06; p = 0.026), ex-smoker (OR: 2.29,
95% CI: 1.22–4.28; p = 0.009), piracetam use (OR: 1.73, 95% CI: 1.18–2.55; p = 0.005), atrial fibrillation
(OR: 3.92, 95% CI: 2.31–8.24; p < 0.001), and large-artery atherosclerosis (OR: 2.68, 95% CI: 1.57–4.60;
p < 0.001).

3.4. Sensitivity Analysis for Possible Interaction Test Among Piracetam and Other Covariates, and the Adjusted
Ratio Difference in Favor of NIHSS Improvement for These Variables
The sensitivity analysis showed that there was no interaction between piracetam and BMI
(p = 0.217). p values for interactions between piracetam and other variables indicate no interaction if p
> 0.05 using logistic regression model. No interactions were found among piracetam and variables
other than BMI such as age (p = 0.691), gender (p = 0.779), smoking habits (p = 0.713), hypertension (p =
0.292), diabetes mellitus (p = 0.622), dyslipidemia (p = 0.765), atrial fibrillation (p = 0.605), and TOAST
(p = 0.942). Therefore, any variables were unnecessary to exclude from multivariate analysis in Table 2
to re-associating piracetam and clinical variables with NIHSS score changes for sensitivity analysis.
Regarding the significant associations of piracetam and clinical variables with NIHSS score
improvement by multivariate analysis in Table 2, adjusted ratio difference was calculated in the
item with statistically significant comparison with its reference of each clinical category (Table 3). Of
the 1351 ischemic stroke patients included in this study, NIHSS scores were improved in 131 cases
(9.7%) and the odds were 0.11 (131/1220). If no piracetam was given, only 8.1% (72/822 + 72) stroke
patients had improved NIHSS scores and the odds were 0.09 (72/822). Piracetam improved the NIHSS
scores in 12.9% (59/398 + 59) of patients and the odds increased to 0.15 (59/398; an increase of odds
0.06 (0.15–0.09)). In the analysis of the adjusted ratio difference in favor of improvement in NIHSS,
piracetam treatment had 6.4% (95% CI: 2.2%–13.6%) increase for improvement of ischemic stroke as
compared to no piracetam (Table 3). Other conditions that had this advantage, compared to their
control conditions, were underweight 20.3% (95% CI: 4.7%–52.2%), current smoker 7.5% (95% CI:
0.6%–18.9%), ex-smoker 11.9% (95% CI: 2.0%–30.2%), and large-artery atherosclerosis 8.6% (95% CI:
J. Clin. Med. 2019, 8, 122 8 of 13

2.9%–18.4%). However, the factor most associated with NIHSS improvement for stroke patients was
atrial fibrillation 23.4% (95% CI: 2.5%–57.9%) (Table 3).

Table 3. Subgroup analysis of clinical variables for the associations of piracetam with NIHSS
score improvement and the adjusted ratio difference in each clinical category in Taiwan ischemic
stroke patients.

Adjusted Ratio
NIHSS NIHSS 95% CI Difference of
Rate
Variables Improved NotImproved Lower-Upper SE p Value * NIHSS
(Proportion)
(n = 131) (n = 1220) Rate Improvement
(95% CI) †
Age (years)
<75 56 713 0.073 0.054–0.091 0.009 0.061
-
≥75 75 507 0.129 0.102–0.156 0.014 0.025
Gender
male 46 433 0.096 0.070–0.122 0.013 0.273
-
female 85 787 0.097 0.078–0.117 0.010 0.007
BMI
normal weight 59 596 0.090 0.068–0.112 0.011 0.016 reference
underweight 14 42 0.250 0.137–0.363 0.058 0.425 20.3% (4.7%–52.2%)
overweight 45 443 0.092 0.067–0.118 0.013 0.688 -
obese 9 117 0.071 0.026–0.116 0.023 0.035 -
Smoking
non-smoker 70 761 0.084 0.065–0.103 0.010 0.123 reference
current smoker 40 327 0.109 0.077–0.141 0.016 0.074 7.5% (0.6%–18.9%)
ex-smoker 21 132 0.137 0.083–0.192 0.028 0.033 11.9% (2.0%–30.2%)
Piracetam
negative 72 822 0.081 0.063–0.098 0.009 reference
-
positive 59 398 0.129 0.098–0.160 0.016 6.4% (2.2%–13.6%)
Hypertension
negative 29 249 0.104 0.070–0.140 0.018 0.866
-
positive 102 971 0.095 0.078–0.113 0.009 0.004
Diabetes mellitus
negative 76 625 0.108 0.085–0.131 0.012 0.018
-
positive 55 595 0.085 0.063–0.106 0.011 0.124
Dyslipidemia
negative 43 374 0.103 0.074–0.132 0.015 0.280
-
positive 88 846 0.094 0.075–0.113 0.010 0.013
Atrial fibrillation
negative 82 1025 0.074 0.059–0.090 0.008 0.020 reference
positive 49 195 0.201 0.151–0.251 0.026 0.131 23.4% (2.5%–57.9%)
TOAST
Small-vessel
21 411 0.049 0.028–0.069 0.010 0.106 reference
occlusion
large-artery
51 355 0.126 0.093–0.158 0.016 0.145 8.6% (2.9%–18.4%)
atherosclerosis
cardioembolism 34 159 0.176 0.122–0.230 0.027 0.106 -
others 25 295 0.078 0.049–0.108 0.015 0.453 -
Statistical analysis: logistic regression model. * p value, to define the statistical significance for the associations of
piracetam with NIHSS score improvement in each subgroup of each clinical category in subgroup analysis using
logistic regression model. † The adjusted ratio difference in favor of improvement in NIHSS that was calculated as
I0 × (AOR-1), for which AOR is the adjusted odds ratio in case subgroup and I0 the unadjusted odds for patients
in control subgroup. The adjusted ratio difference was only calculated in the item with statistically significant
comparison with its reference of each clinical category using multivariate analysis in Table 2, otherwise it was not
showed. Abbreviations: NIHSS, National Institute of Health Stroke Scale; BMI, body mass index; TOAST, Trial of
Organization 10,172 in Acute Stroke Treatment classification; SE, standard error; 95% CI, 95% confidence interval.

3.5. Subgroup Analysis

Using subgroup analysis of clinical variables, piracetam treatment improving NIHSS scores was
found when it was added in the following conditions (Figure 2 and Table 3): age ≥75 years old (OR:
1.86, 95% CI: 1.08–3.20, p = 0.025), male (OR: 1.94, 95% CI: 1.20–3.15, p = 0.007), normal weight (OR:
1.99, 95% CI: 1.13–3.48, p = 0.016), obesity (OR: 9.21, 95% CI: 1.17–72.23, p = 0.035), ex-smoker (OR: 3.36,
95% CI: 1.10–10.21, p = 0.033), hypertension (OR: 1.93, 95% CI: 1.24–3.00, p = 0.004), no diabetes mellitus
(OR: 1.84, 95% CI: 1.11–3.06, p = 0.018), dyslipidemia (OR: 1.83, 95% CI: 1.14–2.94, p = 0.013), and no
 J. Clin. Med. 2019, 8, 122 9 of 13

atrial fibrillation (OR: 1.75, 95% CI: 1.09–2.81, p = 0.020). The different TOAST classifications showed
J.no obvious
Clin. favorable
Med. 2019, OR in
8, x FOR PEER NIHSS improvement, while adding piracetam (Figure 2 and Table9 3).
REVIEW of 13

Subgroup
Figure2.2.Subgroup
Figure analysis
analysis of of epidemiological
epidemiological andand comorbidity
comorbidity variables
variables for for
the the associations
associations of
of piracetam
piracetam withwith NIHSS
NIHSS score
score improvement.
improvement. Association
Association of of piracetamtreatment
piracetam treatmentwith
withNIHSS
NIHSS
improvementwas
improvement wasevaluated
evaluatedinineach eachsubgroup
subgroupinineach
eachcategory.
category.Logistic
Logisticregression
regressionmodel
modelwaswasused
used
for statistical analysis. NIHSS, National Institute of Health Stroke Scale; BMI, body
for statistical analysis. NIHSS, National Institute of Health Stroke Scale; BMI, body mass index; DM,mass index; DM,
diabetes mellitus;
diabetes mellitus; Af,
Af,atrial
atrialfibrillation; TOAST,
fibrillation; TrialTrial
TOAST, of Organization 10,172 in
of Organization AcuteinStroke
10,172 AcuteTreatment
Stroke
classification;
Treatment 1, small-vessel
classification; occlusion; 2,
1, small-vessel large-artery
occlusion; atherosclerosis;
2, large-artery 3, cardioembolism;
atherosclerosis; 4, others; (−),
3, cardioembolism;
4,negative;
others; (+),
(−), positive;
negative;AOR,(+), adjusted
positive; odds
AOR,ratio, adjusted
adjusted among
odds theadjusted
ratio, categories including
among the age, gender,
categories
BMI, smoking habit, hypertension, DM, dyslipidemia, Af and TOAST; 95% CI, 95%
including age, gender, BMI, smoking habit, hypertension, DM, dyslipidemia, Af and TOAST; 95% CI, confident interval.
95% confident interval.
4. Discussion
4. Discussion
Piracetam treatment could be associated with NIHSS improvement in ischemic stroke patients
in Taiwan based on univariate and multivariate analyses in this study. The epidemiological and
Piracetam treatment could be associated with NIHSS improvement in ischemic stroke patients
comorbidity characteristics of patients with piracetam and without piracetam were balanced based
in Taiwan based on univariate and multivariate analyses in this study. The epidemiological and
on standardized difference. Age is an important variable and has been used for the evaluation of
comorbidity characteristics of patients with piracetam and without piracetam were balanced based
the effects of intravenous thrombolysis with alteplase for acute ischemic stroke [19]. Although the
on standardized difference. Age is an important variable and has been used for the evaluation of the
standardized difference of age in this study was 0.130 (13%) and beyond 10%, it was below 0.2 (20%),
effects of intravenous thrombolysis with alteplase for acute ischemic stroke [19]. Although the
which indicates a 15% of non-overlap in the two age subgroups distribution. It has been reported that
standardized difference of age in this study was 0.130 (13%) and beyond 10%, it was below 0.2 (20%),
which indicates a 15% of non-overlap in the two age subgroups distribution. It has been reported that
an effect size is associated with three different measures of non-overlap between two populations
and effect size of 0.2 represents a small effect size [20–22].
A study by Piracetam in Acute Stroke Study (PASS) in 1997 showed improvement in
neurological symptoms and Barthel Index scores at 12 weeks, but there was no effect in 1-month
J. Clin. Med. 2019, 8, 122 10 of 13

an effect size is associated with three different measures of non-overlap between two populations and
effect size of 0.2 represents a small effect size [20–22].
A study by Piracetam in Acute Stroke Study (PASS) in 1997 showed improvement in neurological
symptoms and Barthel Index scores at 12 weeks, but there was no effect in 1-month mortality [23].
Cochrane Review pointed out that piracetam is ineffective in patients with presumed ischemic
stroke, although other potential beneficial effects of piracetam remain unclear because of insufficient
well-controlled studies [24]. Experiments in animals suggested that piracetam could have beneficial
effects in patients with acute stroke [25]. A meta-analysis of studies in models of stroke/cerebral
ischemia in rats also supported the potential effectiveness of piracetam [26]. Piracetam has been
demonstrated to increase brain penetration in ischemic stroke rats and significantly decrease brain
infarct volume [27]. However, it has been approved for use by the Taiwan National Health Insurance
Administration. Piracetam was reported to increase cerebral blood flow and glucose metabolism
in both infarcted and penumbral tissues and to be an effective adjunct of verbal skills in stroke
patients with aphasia (confirmed by neuroimaging tests) [28–30], but it failed to improve visuospatial
and recognition memory, and cognitive functions such as reasoning [31,32]. Other than standard
supportive treatments, neurologists often wish there were ways to improve outcomes in acute ischemic
stroke patients who are presented to the hospital more than 4.5 hours after onset of symptoms, do
not qualify for intravenous thrombolysis, intraarterial thrombectomy, or suffer from deterioration of
clinical presentation.
To date, only risk factors, but no clinical characteristics that are associated with NIHSS score
changes, are reported in ischemic stroke in Taiwan. Age, hypertension, atrial fibrillation, smoking habit,
glucose intolerance, and hypercholesterolemia have been reported to be risk factors for ischemic stroke
according to the Hisayama study [33]. The unique features of this study include the investigation of
baseline epidemiological and comorbidity characteristics as variables that may affect NIHSS score
changes, but not as risk factors of ischemic stroke. Once acute ischemic stroke occurred, underweight,
current smoker, ex-smoker, atrial fibrillation, and large-artery atherosclerosis were associated with
NIHSS improvement in addition to piracetam use, based on the multivariate analysis in this study.
Another unique feature of this study demonstrated that piracetam is beneficial in the following:
age ≥75 years old, male, normal weight or obese, ex-smoker, hypertension, dyslipidemia, no diabetes
mellitus, and no atrial fibrillation by subgroup analysis. It implies that although ischemic stroke
patients with atrial fibrillation have better NIHSS improvement, as compared to those without atrial
fibrillation, patients without atrial fibrillation may have improved NIHSS score after piracetam
treatment. The ischemic stroke patients may have similar association after they take piracetam
treatment in the following conditions: normal weight and obesity. Piracetam may enhance this
association in ex-smoker patients. This shows that ischemic stroke patients, who have multiple risk
factors and are under the current treatment in a specialized ward, do not decrease the chances of
substantial improvement [34]. Piracetam can improve ratio difference for NIHSS by 6.4%. However,
atrial fibrillation can most obviously improve this difference up to 23.4% among the above variables.

5. Limitations
The limitations of this study include there is no way to standardize the use or dosage of oral
piracetam after 3 days intravenous form injection and no follow-up analysis for a longer time period.
There was no follow-up brain imaging in all patients, so it is impossible to determine whether
piracetam injection increases the incidence of cerebral hemorrhage or other sequales that would affect
neurological evaluation [35]. For patients with more severe ischemic stroke (NIHSS score >10) [36],
piracetam might increase the detection of NIHSS improvement but could not guarantee decrease
of overall dependence or disability. The dosage used in this study is based on the manufacturer’s
suggestion and it is appreciably different from the dose used in the PASS [23]. After classification of
each clinical variable, the sample size of each subgroup may not be large enough to draw conclusions.
J. Clin. Med. 2019, 8, 122 11 of 13

6. Conclusions
Piracetam, underweight, current smoker, ex-smoker, atrial fibrillation, and large-artery
atherosclerosis increase the odds ratio of NIHSS improvement for ischemic stroke patients in Taiwan.
Even if patients do not meet above conditions, subgroup analysis reveals that piracetam may improve
NIHSS score for ischemic stroke patients under the following conditions: age ≥75 years old, male,
normal weight, obesity, ex-smoker, hypertension, no diabetes mellitus, dyslipidemia, or no atrial
fibrillation. Additionally, piracetam may enhance the NIHSS improvement in ex-smoker patients.
Thus, the selection of the conditions under which piracetam should be given, and clinical characteristics,
is very important for NIHSS improvement of ischemic stroke patients in Taiwan. This hospital-based
observational study reveals that these factors and conditions are important for the NIHSS score changes
for the ischemic stroke patients in Taiwan, which was unnoticed previously. With the above limitations,
it is necessary to increase the sample size to verify whether the use of piracetam during the acute stage
of ischemic stroke really decreases NIHSS score. Especially after each clinical variable is subdivided,
the smaller numbers of cases may not provide sufficient power for evaluating the OR in this specific
group of patients. Furthermore, the mechanisms, which are involved in the association of piracetam
with improved NIHSS, should be investigated and delineated in the future.

Author Contributions: Conceptualization: P.-H.W., S.-Y.C. and S.-F.Y. Methodology and design: P.-H.W.
and S.-Y.C. Data collection: S.-Y.C. Formal Analysis and interpretation: P.-H.W., Y.-H.W., J.-Y.H. and S.-C.C.
Writing-Original Draft Preparation: S.-Y.C. and S.-F.Y. Writing-Review & Editing: P.-H.W. and J.-W.L. Supervision:
P.-H.W. All named authors have read the manuscript, have agreed to the submission, have participated in the
study to a sufficient extent to be named as authors and agree with the content and presentation of the paper.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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